The goal of this project is to elucidate the developmental function of the receptor tyrosine kinase (RTK) encoded by the c-ret proto-oncogene. RTKs, many of which can act as oncogenes following rearrangement or viral transduction, normally serve as the cellular receptors for a variety of growth and differentiation factors with important roles in development. The c-ret gene, first identified in its rearranged, oncogenic form, appears to encode the receptor for an as yet unidentified ligand. In the mouse embryo, c-ret mRNA is expressed in a subset of the early migrating neural crest cells and their neuronal derivatives, in regions of the central nervous system, and also in the developing excretory system, specifically in the nephric duct, the ureteric bud and the growing tips of the collecting ducts. Newborn mice homozygous for a mutant allele of the c-ret gene, ret-k-, produced through gene targeting in embryonic stem cells, lack the enteric nervous system, and display bilateral renal agenesis or dysgenesis. Thus, the ret protein must play an essential role in the migration, proliferation, differentiation or survival of the enteric neuronal progenitors and their derivatives, as well as in the organogenesis of the kidney, presumably serving as the receptor to a signalling molecule(s) required for development of both the excretory system and the enteric nervous system. We propose to examine the function of the c-ret gene in these developmental processes through a series of studies on the ret-k- mutant mice, as well as through the generation of additional mutant and transgenic strains of mice. In addition, we will attempt to identify and clone the gene encoding the ligand of the c-ret receptor. We propose strategies based on the potential of the ligand to act as a growth factor for cells expressing an exogenous c-ret receptor gene. This work is relevant to our understanding of the relationship between oncogenes and proto-oncogenes, and should also provide new insight into the molecular mechanisms governing the development of the mammalian nervous and excretory systems.